Method for preparation of cefuroxime axetil

ABSTRACT

An improved method for synthesis of cefuroxime axetil of formula (I) in high purity substantially free of the corresponding 2-cephem(Δ 2 )-ester of formula (II) and other impurities. The compound produced is valuable as a prodrug ester of the corresponding cephalosporin-4-carboxylic acid derivative i. e. cefuroxime, particularly suitable for oral administration in various animal species and in man for treatment of infections caused by gram-positive and gram-negative bacteria.

FIELD OF THE INVENTION

[0001] The present invention relates to an improved method for synthesisof cefuroxime axetil of formula (I) in high purity substantially free ofthe corresponding 2-cephem(Δ²)-ester of formula (II) and otherimpurities. The compound produced is valuable as a prodrug ester of thecorresponding cephalosporin-4-carboxylic acid derivative i. e.cefuroxime, particularly suitable for oral administration in variousanimal species and in man for treatment of infections caused bygram-positive and gram-negative bacteria.

BACKGROUND OF THE INVENTION

[0002] One of the ways to improve the absorption of cephalosporinantibiotics which are poorly absorbed through the digestive tract is toprepare and administer the corresponding ester derivatives at the4-carboxylic acid position. The esters are then readily and completelyhydrolysed in vivo by enzymes present in the body to regenerate theactive cephalosporin derivative having the free carboxylic acid at the4-position.

[0003] Among the various ester groups that can be prepared andadministered only a selected few are biologically acceptable, inaddition to possessing high antibacterial activity and broadantibacterial spectrum. Clinical studies on many such potential “prodrugesters” such as cefcanel daloxate (Kyoto), cefdaloxime pentexil tosilate(Hoechst Marion Roussel) and ceftrazonal bopentil (Roche), to name a fewhave been discontinued, while ceftizoxime alapivoxil ((Kyoto) in underPhase III clinical studies. The cephalosporin prodrug esters which havebeen successfully commercialised and marketed include cefcapene pivoxil(Flomox®, Shionogi), cefditoren pivoxil (Spectracef®, Meiji Seika),cefetamet pivoxil (Globocef®, Roche), cefotiam hexetil (Taketiam®,Takeda), cefpodoxime proxetil (Vantin®, Sankyo), cefteram pivoxil(Tomiron®, Toyama) and cefuroxime axetil (Ceftin® and Zinnat®, GlaxoWellcome).

[0004] Typically, such (3,7)-substituted-3-cephem-4-carboxylic acidesters represented by formula (I A) are synthesised by reacting thecorresponding (3,7)-substituted-3-cephem-4-carboxylic acid derivative offormula (III A), with the desired haloester compound of formula (IV A)in a suitable organic solvent. The synthesis is summarised in Scheme-I,wherein in compounds of formula (I A), (II A), (III A) and (IV A) thegroups R¹ and R² at the 3- and 7-positions of the β-lactam ring aresubstituents useful in cephalosporin chemistry; R³ is the addendum whichforms the ester function and X is halogen.

[0005] However, the esterification reaction which essentially involvesconversion of a polar acid or salt derivative to a neutral ester productinvariably produces the corresponding (3,7)-substituted-2-cephem(Δ²)-4-carboxylic acid ester derivative of formula (II A) in varyingamounts, arising out of isomerisation of the double bond from the 3-4position to the 2-3 position as well as other unidentified impurities.

[0006] It has been suggested [D. H. Bentley, et. al., Tetrahedron Lett.,1976, 41, 3739] that the isomerisation results from the ability of the4-carboxylate anion of the starting carboxylic acid to abstract a protonfrom the 2-position of the 3-cephem-4-carboxylic acid ester formed,followed by reprotonation at 4-position to give the said Δ²-ester. Ithas also been suggested [R. B. Morin, et. al., J. Am. Chem. Soc., 1969,91, 1401; R. B. Woodward, et. al., J. Am. Chem. Soc., 1966, 88, 852]that the equilibrium position for isomerisation is largely determined bythe size of the ester addendum attached at the 4-carboxylic acidposition.

[0007] The 2-cephem-4-carboxylic acid esters of formula (II A) are notonly unreactive as antibacterial agents but are undesired by-products.Pharmacopoeias of many countries are very stringent about the presenceof the 2-cephem analogues in the finished sample of(3,7)-substituted-3-cephem-4-carboxylic acid esters and set limits forthe permissible amounts of these isomers. Due to the structuralsimilarity of the 2-cephem and 3-cephem analogues it is very difficultto separate the two isomers by conventional methods, such aschromatography as well as by fractional crystallisation. In addition tothis removal of other unidentified impurities formed in the reaction,entails utilisation of tedious purification methods, thus overallresulting in,

[0008] a) considerable loss in yield, increasing the cost of manufactureand

[0009] b) a product of quality not conforming to and not easily amenablefor upgradation to pharmacopoeial standards.

[0010] Several methods are reported in the prior art for synthesis ofcefuroxime axetil of formula (I) and various(3,7)-substituted-3-cephem-4-carboxylic acid esters of formula (I A),with attempts to minimise the unwanted Δ²-isomers formed in suchreactions as well as conversion of the Δ²-isomer thus formed back to thedesired Δ³-isomer. The prior art methods can be summarised as follows:

[0011] (i) U.S. Pat. No. 4,267,320 (Gregson et. al.) describes a methodfor synthesis of cefuroxime axetil comprising reaction of cefuroximeacid or its alkali metal salts or onium salts with (R,S)-1-acetoxyethylbromide in an inert organic solvent selected from N,N-dimethylacetamide,N,N-dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile andhexamethylphosphoric triamide at a temperature in the range of −50 to+150° C. The patent mentions that when alkali metal salts, speciallypotassium salt of cefuroxime acid are employed the reaction can becarried out in a nitrile solvent in the presence of a crown ether. Whencefuroxime acid is employed the reaction is carried out in the presenceof a weak inorganic base such as sodium carbonate or potassiumcarbonate, which is added prior to the addition of the haloester. Thepatent further mentions that the use of potassium carbonate inconjunction with the haloester, specially the bromo or iodo ester ispreferred since it helps to minimise the formation of the Δ²-isomer.Ideally, substantially equivalent amounts of cefuroxime acid and thebase is employed.

[0012] The U.S. Pat. No. 4,267,320 also describes methods, wherein thesaid esterification is carried out in the presence of an acid bindingagent, which serve to bind hydrogen halide liberated in the reaction,thereby controlling the formation of the Δ²-isomer. The acid bindingagents that are utilised include a tertiary amine base such astriethylamine or N,N-dimethylamine; an inorganic base such as calciumcarbonate or sodium bicarbonate and an oxirane compound such as ethyleneoxide or propylene oxide.

[0013] However, from the examples provided in the above patent the yieldof cefuroxime axetil and other (3,7)-substituted-3-cephem-4-carboxylicacid esters obtained is found to be only of about 50%, implyingformation of substantial amounts of impurities in the reaction. Indeed,when cefuroxime acid is reacted with (R,S)-1-acetoxyethyl bromide in thepresence of 0.55 molar equivalents of sodium carbonate or potassiumcarbonate in N,N-dimethylacetamide as solvent, as per the processdisclosed in this patent, it is found that substantial amounts of theΔ²-isomer in a proportion ranging from 10-22% is formed, in addition toother unknown impurities. Also, substantial amounts of the startingcefuroxime acid remains unreacted even after 5 hrs of reaction.Isolation of the product generally affords a gummy material, whichresists purification even after repeated crystallisations.

[0014] Moreover, the use of the acid binding agents mentioned in theabove patent, specially tertiary amines and inorganic bases lead tocleavage of the β-lactam ring and also promote the undesiredΔ²-isomerisation, thereby enhancing the level of impurities formed inthe reaction.

[0015] (ii) (GB Patent No. 2 218 094 describes a method by which theΔ²-isomers formed during esterification can be converted back to thedesired Δ³-isomers. The method comprises of oxidation of thedihydrothiazine ring in the mixture of Δ²- and Δ³-cephalosporin acidesters to the corresponding sulfoxide derivatives with suitableoxidising agents, whereby the Δ²-isomer gets isomerised to thecorresponding Δ³-isomer during oxidation and the Δ³-cephalosporin acidester sulfoxide is isolated. The sulfide group is regenerated back byreduction of the sulfoxide function with suitable reducing agents.

[0016] Typically, the oxidation is carried out using m-chloroperbenzoicacid and the reduction achieved by use of an alkali metal halide inpresence of acetyl chloride in presence of an inert organic solvent orby use of a phosphorous trihalide.

[0017] Although, this method provides the desired Δ³-isomers in goodpurity, it cannot be considered as an industrially feasible method sinceit involves a two step process of oxidation and reduction, isolation ofthe intermediate products at each stage and necessary purifications, allresulting in considerable loss of the desired product and increase inthe cost of manufacture. Moreover, the use of acetyl halide andphosphorous trihalide in the reduction step cannot be applied tocephalosporin derivatives that are sensitive to these reagents.

[0018] A similar method has been reported by Kaiser et. al. in J. Org.Chem., 1970, 35, 2430.

[0019] (iii) Mobasherry et. al. in J. Org. Chem., 1986, 51, 4723describe preparation of certain Δ³-cephalosporin-4-carboxylic acidesters by reaction of the corresponding 3-cephem-4-carboxylic acids (inturn prepared form the corresponding carboxylic acid alkali metal salts)with an haloester in presence of 1.1 eq of sodium carbonate in thepresence 1.2-1.5 eq of an alkyl halide and in presence of a solventcomprising of a mixture of N,N-dimethylformamide and dioxane. Theauthors claim that the method provides of Δ³-cephalosporin-4-carboxylicacid esters unaccompanied by the corresponding Δ²-isomer.

[0020] However, the method involves an additional step in that thestarting 3-cephem-4-carboxylic acid ester derivatives are obtained fromthe corresponding alkali metal salts prior to reaction. In addition,longer reaction times of about 24 hrs coupled with the fact that itutilises dioxane, a potent carcinogen, not recommended by InternationalConference on Harmonisation (ICH) on industrial scale renders the methodunattractive commercially.

[0021] Moreover, on duplication of the method exactly as described inthe article it is found that about 3-4% of the corresponding Δ²-isomeris indeed formed in the reaction in addition to other unidentifiedimpurities. Also, substantial amounts of the starting cephalosporincarboxylic acid is recovered unreacted.

[0022] (iv) Shigeto et. al. in Chem. Pharm. Bull., 1995, 43(11), 1998have carried out the esterification of certain7-substituted-3-cephem-4-carboxylic acid derivatives with 1-iodoethylisopropyl carbonate in a solvent system containing a mixture ofN,N-dimethylformamide and dioxane in a 3:5 ratio. A conversion to thecorresponding 3-cephem-4-carboxylate ester was achieved in only 34%, outof which the Δ²-isomer amounted to about 8%.

[0023] Esterification of7-formamido-3-(N,N-dimethylcarbamoyloxy)methyl-3-cephem-4-carboxylicacid sodium salt with a suitable haloester in presence of solvents suchas N,N-dimethylacetamide and N,N-dimethylformamide, with formation ofabout 0.8 to 3.0% of the Δ²-isomer is also reported in the above articleby Shigeto et. al. The 7-formamido group was cleaved under acidicconditions to give the corresponding 7-amino derivative contaminatedwith only about 0.4% of the corresponding Δ²-isomer. The minimisation ofthe percentage of Δ²-isomer is attributed to the relative unstability of7-amino-2-cephem-4-carboxylic acid esters in acidic conditions,facilitating isomerisation of the 2-cephem intermediate to the 3-cephemderivative.

[0024] However, the method does not have a general application,especially for synthesis of commercially valuable cephalosporinderivatives containing hydroxyimino or alkoxyimino substituents in the7-amino side chain addendum, since these oxyimino functions exhibit atendency to isomerise from the stable (Z)-configuration to therelatively undesirable (E)-configuration under acidic conditions. Thiswould render separation of the two isomers cumbersome. Moreover, longerreaction times of about 18-20 hrs to effect the isomerisation of thedouble bond from the 2-position to the 3-position and use of toxicdioxane as solvent impose further limitations on the method.

[0025] (v) Demuth et. al. in J. Antibiotics, 1991, 44, 200 have utilisedthe N,N-dimethylformamide-dioxane system in the coupling of1-iodocephem-4-nitrobenzyl ester with naldixic acid sodium salt andrecommend use of dioxane since it reduces the basicity of the quinolonecarboxylate and lowers the polarity of the reaction medium.

[0026] However, low yields of about 35% and use of toxic dioxane makesthe method of little industrial application.

[0027] (vi) Wang et. al. in U.S. Pat. No. 5,498,787 claim a method forpreparation of certain (3,7)-substituted-3-cephem-4-carboxylic acidprodrug esters, unaccompanied by the analogous 2-cephem esterscomprising reaction of the corresponding(3,7)-substituted-3-cephem-4-carboxylic acid alkali metal salts withsuitable haloesters in the presence of catalytic amounts of aquarternary ammonium or quarternary phosphonium salt. Among the prodrugesters covered in this patent is cefuroxime axetil.

[0028] U.S. Pat. No. 5,498,787 claims that among the quarternaryammonium salts, such salts with acid counter ion, specially tetrabutylammonium sulfate (TBA⁺HSO₄ ⁻) is the most preferred. When the molarratio of TBA⁺HSO₄ ⁻/cefuroxime sodium was above 0.40 no Δ²-isomer wasdetected, when the said molar ratio was below 0.40 and near about 0.20the molar ratio of Δ²/Δ³ isomers formed was about 2.0%. When no TBA⁺HSO₄⁻ was added the molar ratio of Δ²/Δ³ isomers formed was about 10.0%.Examples 1 and 2 of this patent illustrate the esterification ofcefuroxime sodium in presence of TBA⁺HSO₄ ⁻ and indicate that theΔ²-isomer was not detected after 3-12 hours of reaction. The same patentalso establishes the superiority of TBA⁺HSO₄ ⁻ over other salts,specially tetrabutyl ammonium iodide (TBA⁺I⁻) since use of the lattersalt resulted in considerable isomerisation of the double bond givingthe undesired Δ²-isomer in predominant amounts.

[0029] The present inventors have, however, found that when cefuroximesodium is reacted with (R,S)-1-acetoxyethyl bromide in the presence oftetrabutylammonium sulfate (TBA⁺HSO₄ ⁻) as per the method covered inU.S. Pat. No. 5,498,787 the same did not necessarily result in theproduction of the desired Δ³ isomer free of the undesired Δ² isomer andother impurities. Also, such process had limitations in that thereaction could not be completed at times even at the end of 5.0 hrs.Moreover, the separation of the impurities, from the product provedcumbersome and could not be removed from the product even aftersuccessive crystallisations.

[0030] (vii) H. W. Lee et. al., Syntheic Communications, 1998, 28(23),4345-4354 have demonstrated a method essentially similar to that claimedin U.S. Pat. No. 5,498,787. The method of preparation of various estersof cefotaxime consists of reacting cefotaxime sodium with the requisitehaloester compound in a suitable solvent and in presence of quarternaryammonium salts as phase transfer catalysts. It is claimed that when noquarternary ammonium salts are added the molar ratio (%) of Δ²/Δ³isomers formed is about 10%. The formation of Δ²-isomer is minimisedwhen quarternary ammonium salts are added and particularly when themolar ratio of TBA⁺HSO₄ ⁻/cefotaxime sodium employed is 0.80 theformation of the Δ²-isomer is completely inhibited.

[0031] However, this method requires long hours (˜18-24 hrs) and iscarried out at higher temperatures (40-45° C.) and as such may not besuitable for cephalosporin derivatives that are sensitive to heat.

[0032] (viii) H. W. Lee et. al. in Synthetic Communications, 1999,29(11), 1873-1887 demonstrate a method for preparation of number of(3,7)-substituted-3-cephem-4-carboxylic acid esters comprising reactingthe corresponding (3,7)-substituted-3-cephem-4-carboxylic acidderivatives with a base selected form cesium carbonate or cesiumbicarbonate either used alone or in combination with potassiumcarbonate, sodium carbonate, potassium bicarbonate and sodiumbicarbonate. The authors established that the formation of Δ²-isomerscould be minimised by utilisation of a solvent combination ofN,N-dimethyl formamide and dioxane. The use of the latter mentionedsolvent i. e. dioxane was expected to lower polarity of the reactionmedium and thereby reduce the basicity of the transient3-cephem-4-carboxylate anion formed in the reaction and thus preventingthe isomerisation of the double bond from the 3-4 position to the 2-3position.

[0033] The formation of the Δ²-isomer was found to be dependent on theamount of dioxane in the solvent mixture, the more the proportion ofdioxane lesser the degree of isomerisation.

[0034] However, yields of representative esters obtained by the methodare in the range of 45-85%, implying that the reaction is accompanied byformation of substantial amounts of impurities and that theisomerisation is dependent on the nature of the substituent at3α-position of the cephalosporin nucleus as well as on the nature of thehaloester employed. Moreover, the method utilises dioxane, not desirablefor reasons mentioned herein earlier and expensive cesium salts. Thismethod, therefore, also has limited application.

[0035] (ix) Y. S. Cho et. al., in Korean J. Med. Chem., 1995, 5(1),60-63 describe synthesis of several cephalosporin prodrug esters andtheir efficacy on oral administration. The esters were synthesised byreacting the corresponding cephalosporin-4-carboxylic acid derivativewith the respective haloester derivative in presence of cesium carbonateand N,N-dimethylacetamide. The yields of the ester derivatives obtainedare in the range of only 25-56%, indicating formation of substantialamounts of impurities in the reaction.

[0036] Thus, in summary the prior art methods are associated with one ormore of the following shortcomings, which limit their application as anindustrially acceptable method for synthesis of various(3,7)-substituted-3-cephem-4-carboxylic acid esters, speciallycefuroxime axetil. These are, viz.

[0037] a) formation of varying amounts of the undesired2-(Δ²)-cephem-4-carboxylic acid esters, and other unidentifiedimpurities, specially impurities X₁ and X₂ mentioned earlier,

[0038] b) incompleteness of the reaction, resulting in substantialamounts of starting material remaining unreacted,

[0039] c) employment of tedious/costly techniques for separation of theunwanted Δ²-isomer, other unidentified impurities and unreacted startingmaterial,

[0040] d) shortcomings a), b) and c) giving the final product in lowyields and of inferior quality, thereby making the methods commerciallyunviable,

[0041] e) use of carcinogenic and toxic solvents not acceptableindustrially,

[0042] f) use of additives/catalysts as acid binding agents notefficient enough to prevent the Δ³- to Δ²-isomerisation and

[0043] g) lack of general applicability for synthesis of a variety of(3,7)-substituted-3-cephem-4-carboxylic acid esters.

[0044] It is thus the basic object of the present invention to providefor an improved process for manufacture of(3,7)-substituted-3-cephem-4-carboxylic acid esters particularlycefuroxime axetil of formula (I) which would be substantially free ofundesired 2-(Δ²)-cephem-4-carboxylic acid esters and any associatedimpurities.

[0045] It is another object of the present invention to provide for animproved synthesis of (3,7)-substituted-3-cephem-4-carboxylic acidesters, particularly cefuroxime axetil of formula (I), whicheliminates/minimises the aforesaid shortcomings associated with theprior art methods and provides the object compound(s) in highly pureform, suitable for use in pharmaceuticals.

[0046] Another object of the present invention is to provide compoundsof formula (I) in high purity i.e. of quality conforming topharmacopoeial standards.

[0047] Yet further object of the present invention is to provude acost-effective and environmentally benign method for preparation ofcefuroxime axetil of formula (I) in high purity utilising cost effectiveand readily available raw materials and industrially acceptablesolvents.

SUMMARY OF THE INVENTION

[0048] Thus according to the present invention there is provided animproved method for preparation of (R,S)-1-Acetoxyethyl(6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylatei.e. cefuroxime axetil of formula (I), in high purity, substantiallyfree of analogous Δ²-isomer of formula (II) and other impurities

[0049] comprising reacting cefuroxime acid of formula (III)

[0050] with (R,S)-1-acetoxyethyl bromide of formula (IV) and a Group Iand/or II metal carbonate and in the presence of a Group I and/or IIphosphate, hydrogen phosphate or polyphosphate of formula (V),

 M_(m)H_(n)P_(q)O_(r)   (V)

[0051] wherein M is a metal selected from Group I or II; m is 1, 2 or 3;n is 0, 1, 2 or 4; q is 1 or 2 and r is 4, 7 or 8 and in presence of aC₁₋₄ alcohol in the presence of a polar tertiary amide solvent at atemperature ranging from about −30 to +30° C. and subjecting the productthus obtained to desired step of purification.

DETAILED DESCRIPTION OF THE INVENTION

[0052] The embodiments of the present invention is based on theutilisation of the phosphates, hydrogen phosphates or polyphosphates offormula (V) in combination with a C₁₋₄ alcohol to eliminate/minimise theformation of unwanted Δ²-isomer of formula (II) and other unidentifiedimpurities, specially two impurities termed X₁ and X₂ formed during thecourse of the reaction of cefuroxime acid of formula (III) and ahaloester of formula (IV) in the presence of Group I or II metalcarbonates to give cefuroxime axetil of formula (I) in high purity.

[0053] The method of preparation of cefuroxime axetil as per the methodof the present invention is summarised in Scheme-II.

[0054] In a typical method, a solution of cefuroxime acid of formula(III) in a polar tertiary amide solvent is mixed with the Group I or IImetal carbonate; Group I or II metal phosphate, hydrogen phosphate orpolyphosphate of formula (V); (R,S)-1-acetoxyethyl bromide of formula(IV) and a C₁₋₄ alcohol at a temperature ranging from −30 to +30° C. andagitated at a temperature of from about −10 to about +20° C. for about 2to 8 hrs. At the end of the reaction, the reaction mixture is dilutedwith water, and the aqueous portion extracted with a suitable organicsolvent. Evaporation of the solvent gives the object compound of formula(I), which is further purified by crystallisation.

Scheme-II: Method for Preparation of Cefuroxime Axetil as per thePresent Invention

[0055] Preferably, the Group I or II metal phosphate, hydrogen phosphateor polyphosphate may be first added to the solution of cefuroxime acidin the polar solvent, followed by addition of the Group I or II metalcarbonate. To the mixture is slowly added (R,S)-1-acetoxyethyl bromide,pre-mixed with the C₁₋₄ alcohol and the reaction mixture agitated andworked up as mentioned herein before.

[0056] Alternatively, both the Group I or II metal phosphate, hydrogenphosphate or polyphosphate and the Group I or II metal carbonate can beadded to the solution of cefuroxime acid in the aprotic solvent,followed by addition of (R,S)-1-acetoxyethyl bromide, pre-mixed with theC₁₋₄ alcohol and the reaction performed as described herein earlier.

[0057] More preferably, the Group I or II metal carbonate is added firstto the solution of cefuroxime acid in the protic solvent, followed bythe addition of the Group I or II phosphate, hydrogen phosphate orpolyphosphate. To this is then added (R,S)-1-acetoxyethyl bromide,pre-mixed with the C₁₋₄ alcohol and the reaction performed as describedherein earlier.

[0058] The mode of addition of the Group I or II metal carbonate and thephosphate salts as mentioned above does not affect the course of thereaction and all such variations in the mode of addition essentiallyproduce the same result. However, it is most preferred that(R,S)-1-acetoxyethyl bromide be premixed with the C₁₋₄ alcohol beforeaddition of the same to the mixture of cefuroxime acid and Group I or IImetal carbonate and phosphate salts in the polar solvent.

[0059] The polar tertiary amide solvent is selected fromN,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylpropionamide,N,N-diethylacetamide, N,N-diethylformamide and N,N-diethylpropionamide.Amongst these, N,N-dimethylacetamide and N,N-dimethylformamide arepreferred. Furthermore, N,N-diemthylacetamide is preferred overN,N-dimethylformamide since the reaction rate is faster when conductedin the former solvent and takes about 2-4 hrs less time than thereactions conducted in the latter solvent.

[0060] The reaction can be carried out at a temperature ranging fromabout −30 to +30° C. However, when N,N-dimethylacetamide is used as thesolvent, taking into consideration the freezing point of the solvent thereaction is preferably carried out at a temperature ranging from about−10 to +30° C.

[0061] The rate of reaction is also found to be dependent on thereaction temperature, with higher temperature facilitating fasterreaction time. However, at higher temperatures, the isolated producttends to be coloured, which necessiates extra decolourisation steps.This problem is minimised/eliminated when the reaction is performed atlower temperatures and the product obtained is not coloured.Accordingly, most preferably the reaction is carried out a temperatureranging from about −5 to +15° C. in N,N-dimethylacetamide as solvent,which ensures faster reaction rate as well as provides the product ofthe desired colour and quality.

[0062] The alkali and alkaline earth metals from the Group I and IIcarbonates that can be employed are selected from lithium, sodium,potassium, cesium, magnesium and calcium. Conveniently, substantiallyequivalent amounts of the alkali or alkaline earth metal carbonate andcefuroxime acid is employed, e.g. about 0.5 moles of the diacidic baseper mole of cefuroxime. The carbonate salts can also be employed inexcess of equivalent molar ratio and can be employed in a ratio fromabout 0.55 to 1.00 per mole of cefuroxime acid. Preferably, the molarratio is from about 0.55 to 0.90.

[0063] The Group I alkali metal carbonates are preferred over the GroupII alkaline earth metal carbonates and sodium carbonate is the mostpreferred metal carbonate.

[0064] The Group I or II metal phosphates, hydrogen phosphates orpolyphosphates of formula (V) that can be employed in the method includethe respective alkali metal salts of lithium, sodium, potassium andcesium as well as the respective alkaline earth metal salts of magnesiumand calcium. These phosphate salts also include the orthophosphates andmetaphosphates and are cheap and readily available.

[0065] The salts of formula (V) can be employed in molar proportions ofabout 0.10 to about 0.80 equivalents per mole of cefuroxime acid. Thelower and upper limit are equally effective in significantlyminimising/inhibiting the formation of the Δ²-isomer. When theconcentration of compound of formula (V) is below 0.10 molarequivalents, the formation of the Δ²-isomer is found to be more, whileuse of compound (V) in excess of 0.80 molar equivalents is found to slowdown the reaction rate. A preferred range is, however, from about 0.10to 0.40 molar equivalents.

[0066] The Group I or II metal in such phosphates, hydrogen phosphatesand polyphosphates are selected from lithium, sodium, potassium cesium,magnesium and calcium. Amongst these,

[0067] i) the more preferred tribasic phosphates are sodium phosphate(Na₃PO₄), potassium phosphate (K₃PO₄), lithium phosphate (Li₃PO₄),magnesium phosphate [Mg₃(PO₄)₂] and calcium phosphate [Ca₃(PO₄)₂] andall their hydrates thereof.

[0068] ii) the more preferred dibasic hydrogen phosphates are lithiumdihydrogen phosphate (LiH₂PO₄), sodium dihydrogen phosphate (NaH₂PO₄),potassium dihydrogen phosphate (KH₂PO₄), magnesium hydrogen phosphate(MgHPO₄) and all their hydrates thereof.

[0069] iii) the more preferred monobasic hydrogen phosphates includesodium dihydrogen phosphate (Na₂HPO₄), potassium dihydrogen phosphate(K₂HPO₄), magnesium biophosphate (MgH₄PO₈) and calcium biophosphate(CaH₄P₂O₈) and all their hydrates thereof.

[0070] iv) the more preferred polyphosphates include sodiummetaphosphate (Na₄P₂O₇), sodium polymetaphosphate (NaPO₃)_(x), potassiumpyrophosphate (K₄P₂O₇), calcium pyrophosphate (Ca₂P₂O₇) andhydroxylapatite [3Ca₃(PO₄)₂.Ca(OH)₂] and all their hydrates thereof.

[0071] The alkali metal and alkaline earth metal phosphates, hydrogenphosphates and polyphosphates mentioned hereinabove can be employedsingularly or in combination, preferably singularly.

[0072] Of the Group I and Group II metal phosphates, hydrogen phosphatesand polyphosphates the Group I alkali metal salts are preferred.

[0073] Of the Group I alkali metal phosphates, hydrogen phosphates andpolyphosphates the alkali metal hydrogen phosphates are more preferred.

[0074] Of the alkali metal hydrogen phosphates, the alkali metaldihydrogen phosphates such as sodium dihydrogen phosphate (Na₂HPO₄) andpotassium dihydrogen phosphate (K₂HPO₄) are further more preferred.

[0075] Of the alkali metals, sodium is the most preferred and the mostpreferred alkali metal dihydrogen phosphate of the present invention issodium dihydrogen phosphate (Na₂HPO₄).

[0076] The C₁₋₄ alcohol employed in the invention is selected frommethanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol andtert-butanol. These alcohols completely eliminate the formation of theunidentified impurities, viz. impurities X₁ and X₂ formed in thereaction

[0077] Typically, the alcohol is mixed with the haloester, viz.(R,S)-1-acetoxyethyl bromide prior to esterification, at a temperatureranging from about 15 to 40° C. The alcohol can be employed in 0.03 to0.15 molar equivalents per mole of cefuroxime acid. The lower limitcompletely inhibits the formation of the abovementioned unidentifiedimpurities, X₁ and X₂. Employment of the alcohol in proportions up toand above the upper limit not only completely inhibits the formation ofthe impurities, X₁ and X₂, but does not create any adverse effect in thereaction, and more importantly does not lead to formation of additionalimpurities. However, about 0.5 to 1.0% of total impurities are formedwhen the C₁₋₄ alcohol is used below 0.03 molar equivalents per mole ofcefuroxime acid. Preferably, the alcohol is employed from about 0.04 to0.11 molar equivalents per mole of cefuroxime acid. All the C₁₋₄alcohols that are employed in the method are equally effective. However,methanol is the most preferred.

[0078] The effect of utilising combination of the Group I or II metalphosphates, hydrogen phosphates or polyphosphates and the C₁₋₄ alcoholin elimination/minimisation of the Δ²-isomer of formula (II) and theunidentified impurities X₁ and X₂ and any other impurity formed duringthe esterification of cefuroxime acid of formula (III) with(R,S)-1-acetoxyethyl bromide of formula (IV) and a Group I or II metalcarbonate can be seen from the following non-illustrative resultssummarised in Table-I.

[0079] The (R,S)-1-acetoxyethyl bromide of formula (IV) used for theesterification is employed in a ratio of about 1.5-2.5 molar equivalentsper mole of cefuroxime acid, preferably in a ratio of about 1.8-2.0molar equivalents.

[0080] The haloester of formula (IV) is prepared by methods known in theart.

[0081] Since the halo esters employed have one chiral centre and areobtained and utilised for the alkylation reaction as a mixture of (R)-and (S)-isomers, the cefuroxime axetil of formula (I) is obtained as amixture of two diastereomers. Commercially cefuroxime TABLE I Thereaction of Cefuroxime acid (III) with (R, S)-1-acetoxyethyl bromide**(IV) and Group I or II in metal carbonates in the presence of Group I ormetal phosphates, hydrogen phosphates or polyphosphates of fomula (V)and a C₁₋₄ alcohol in N,N-dimethylacetamide as solvent to giveCefuroxine axetil (Δ³-isomer, 1). Group HPLC analysis* of reaction Yieldof I/IImetal Compound C₁₋₄ mass at end of reation Isolated Carbonate (V)alcohol Reaction Reaction % unreacted % Δ³- % Δ²- % % (I) Sr. (M eq of(M eq of (M eq of Temperature Time Cefuroxime isomer isomer impurityimpurity (% No. (III) (III) (III) (° C.) (hrs.) acid (III) (I) (II) X₁X₂ molar) 01 K₂CO₃ — — 0 5.00 10.63 81.87 2.88 2.24 2.58 75.00 (0.75)(sticky solid) 02 K₂CO₃ — — 0-5 4.50 8.09 80.27 4.49 4.59 1.84 62.50(0.50) (sticky solid) 03 Na₂CO₃ — Na₂HPO₄ 0-5 3.00 3.55 85.18 1.50 4.064.00 87.50 (0.80) (0.10) 04 Na₂CO₃ — CH₃OH 0-5 4.00 8.77 78.76 9.80 — —58.30 (0.55) (0.20) 05 Na₂CO₃ — CH₃OH 0 10.0 7.10 83.70 4.90 — — 81.37(0.70) (0.20) 06 K₂CO₃ K₂HPO₄ CH₃OH 0 4.00 2.00 93.90 1.30 — — 87.50(0.69) (0.10) (0.20) 07 K₂CO₃ K₂HPO₄ CH₃OH 0 4.00 2.90 94.15 1.10 — —88.10 (0.68) (0.4−) (0.75) 08 Na₂CO₃ NaH₂PO₄ C₂H₅OH 0 5.50 2.50 93.500.90 — — 87.90 (0.80) (0.15) (0.80) 09 Na₂CO₃ NaH₂PO₄ CH₃OH 0 5.00 2.8092.00 1.10 — — 87.00 (0.80) (0.15) (0.62) 10 Na₂CO₃ Ca(H₂PO₄)₂ CH₃OH 06.00 8.20 86.90 0.83 — — −81.30 (0.75) (0.15) (0.62) 11 Na₂CO₃ Na₄P₂O₇CH₃OH 0-5 5.00 3.90 91.60 1.00 — — 86.10 (0.80) (0.15) (0.4) 12 Na₂CO₃Na₄P₂O₇ CH₃OH 0-5 4.50 4.60 91.30 0.96 — — 86.00 (0.80) (0.40) (0.62) 13Na₂CO₃ Na₃PO₄ CH₃OH 0-5 3.50 5.00 90.70 1.50 — — 85.50 (0.80) (0.15)(0.62) 14 Na₂CO₃ Na₂HPO₄ CH₃OH 0-5 7.00 1.20 94.60 1.00 — — 88.10 (0.80)(0.80) (0.41) 15 Na₂CO₃ Na₂HPO₄ CH₃OH 0-5 7.00 1.10 94.30 1.12 — — 87.90(0.72) (0.60) (0.41) 16 Na₂CO₃ Na₂HPO₄ CH₃OH 0-5 6.30 1.10 94.00 1.20 —— 87.50 (0.80) (0.40) (0.40) 17 Na₂CO₃ Na₂HPO₄ CH₃OH 0-5 6.00 1.29 93.801.41 — — 87.10 (0.77) (0.12) (0.40) 18 Na₂CO₃ Na₂HPO₄ CH₃OH 0-5 1.451.92 93.20 1.58 — — 86.90 (0.80) (0.10) (0.40) 19 Na₂CO₃ Na₂HPO₄ CH₃OH0-5 4.30 1.66 93.93 1.20 — — 87.80 (0.80) (0.40) (0.40) 20 Na₂CO₃NaH₂PO₄ C₂H₅OH 0-5 5.50 2.50 93.50 1.00 — — 87.80 (0.80) (0.15) (0.80)21 Na₂CO₃ Na₄P₂O₇ Iso- 0-5 4.50 4.60 91.30 0.96 — — 86.10 (0.8) (0.40)butanol (0.50) 22 Na₂CO₃ CaH₂PO₄ n-butanol 0-5 6.00 8.20 86.90 0.83 — —85.41 (0.75) (0.15) (0.87) 23 K₂CO₃ K₂HPO₄ CH₃OH 0 4.00 2.90 94.15 1.10— — 88.80 (0.68) (0.40) (0.75) 24 Na₂CO₃ NaH₂PO₄ CH₃OH 0 6.00 3.90 93.790.83 — — 88.68 (0.80) (0.15) (0.62) 25 Na₂CO₃ Na₄P₂O₇ CH₃OH 0-5 5.003.90 93.60 1.00 — — 88.40 (0.80) (0.15) (0.40) 26 Na₂CO₃ Na₂HPO₄ CH₃OH0-5 5.00 4.00 91.94 1.40 0.63 0.63 87.68 (0.80) (0.10) (0.20) 27 Na₂CO₃Na₂HPO₄ CH₃OH 0-5 5.00 3.80 91.30 1.02 1.11 1.12 86.78 (0.80) (0.10)(0.10) 28 Na₂CO₃ TBA⁺HSO₄ ⁻ CH₃OH R.T. 7.50 4.00 88.30 4.30 — — 70.83(0.80) (0.20) (0.20) 29 Na₂CO₃ TBA⁺HSO₄ ⁻ CH₃OH R.T. 8.50 6.60 86.903.50 — — 66.66 (0.80) (0.40) (0.20) 30 Na₂CO₃ TBA⁺HSO₄ ⁻ CH₃OH R.T. 8.03.10 86.40 5.10 — — 62.50 (0.80) (0.10) (0.20)

[0082] axetil and other prodrug esters such as cefpodoxime proxetil andcefotiam hexetil are sold as a diastereomeric mixture.

[0083] After the reaction, the product is isolated by first dilutingwith water and extracted into a water immiscible organic solvent.Solvents in which the prodrug esters are easily soluble are preferredand these include dichloroethane, dichloromethane, ethyl acetate andmethyl isobutyl ketone. The product can be isolated by evaporation ofthe solvent.

[0084] The Δ²-isomer formed in the reaction can be easily removed bycrystallisation of the solid thus obtained either from the same solventor from a mixture of solvents selected from dichloroethane,dichloromethane, ethyl acetate, methyl isobutyl ketone, hexane, toluene,xylene, diisopropyl ether and tertiary butylmethyl ether. A mixture ofethyl acetate with toluene or xylene is the most preferred.

[0085] Cefuroxime axetil obtained by the present method is a crystallinematerial, the X-ray (powder) diffraction of which matches exactly withthe product obtained by the process described by Gregson et. al. in U.S.Pat. No. 4,267,320.

[0086] Cefuroxime axetil obtained in high yields of about 85-92% containthe undesired Δ²-isomer, within the pharmacopoeially acceptable limits.Typically, the product after crystallisation contains only <0.10% of theΔ²-isomer, a value very well below the prescribed pharmacopoeial limits.

[0087] The embodiments of the invention can be best understood from thefollowing non-limiting examples.

EXAMPLE-1 Preparation of (R,S-1-Acetoxyethyl-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate(Cefuroxime axetil, I): Without use of Group I/II metal phosphate andC₁₋₄ alcohol

[0088] (R,S)-1-Acetoxyethyl bromide (1.6 gms; 0.0094 moles) was added toa mixture of cefuroxime acid (2 gms; 0.0047 moles) and potassiumcarbonate (0.326 gms; 0.00235 moles) in N,N-dimethylacetamide (10 ml) at5° C. and stirred at 0 to 20° C. for 180 minutes. Ethyl acetate wasadded to the reaction mixture, followed by 3% aqueous sodium bicarbonatesolution (15 ml). The organic layer containing the title product, Δ²isomer (8.51%) and unidentified impurities (X₁—1.86% and X₂—3.54%) wasseparated and washed with 10% aqueous NaCl solution. The organic solventwas evaporated off under vacuum to give 1.08 gms (44.90%) of the titlecompound as a gummy solid.

[0089] HPLC analysis: Purity (compound I)—89.11%; Impurities: Δ² isomer(II)—8.51%, X₁—1.86% and X₂—3.54%

EXAMPLE-2 Preparation of (R,S-1-Acetoxyethyl-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate(Cefuroxime axetil, I): in presence of disodium hydrogen phosphate andmethanol

[0090] (R,S)-1-Acetoxyethyl bromide (3.94 gms; 0.0235 moles) pre-mixedwith methanol (0.15 gms; 0.0047 moles) was added to a stirred mixture ofcefuroxime acid (5 gms; 0.0118 moles), sodium carbonate (0.94 gms;0.0088 moles) and disodium hydrogen phosphate (1.0 gms; 0.007 moles) inN,N-dimethylacetamide (20 ml) at 0° C. The mixture was stirred at 0 to20° C. for 180 minutes. Ethyl acetate was added to the reaction mixture,followed by 3% aqueous sodium bicarbonate solution (25 ml). The organiclayer was separated and washed with 10% aqueous sodium chloridesolution. The organic extract was stirred with activated charcoal (0.5gms) for 30 minutes and filtered through a celite bed. The organic layerwas evaporated under vacuum and the solid obtained crystallised from amixture of ethyl acetate/xylene. The crystallised material was filteredand dried at 40 to 45° C. under vacuum to give 5.26 gms (87.5%) of thetitle compound.

[0091] HPLC analysis: Purity (compound I) ≧96.00%; Impurities: Δ² isomer(II)—<0.10%, X₁ and X₂—NIL

[0092] [α]_(D) (1% Dioxan): +37°

[0093] IR (KBr): 3500, 3417, 1780, 1749 cm⁻¹

[0094]¹H NMR (d⁶-DMSO; δ): 1.46 (bd, 3H, CH₃), 2.04 (s, CH₃CO), 2.05 (s,CH₃CO), 3.58 (q, CH₂S), 3.88 (s, CH₃O), 4.69 (dd, CH₂O; J=4 Hz), 4.78(dd, CH₂O, J=1 Hz), 5.075 (t, 1H, 6H), 5.85 (m, 1H, 7H), 6.6-6.7 (m,2H), 6.89 (q, CH₃—CH), 7.01 (q, CH₃CH), 7.82 (d, 1h) and 9.60 (dd, 1H,CONH).

EXAMPLE-3 Preparation of(R,S-1-Acetoxyethyl-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate(Cefuroxime axetil, I): in presence of sodium dihydrogen phosphate andethanol

[0095] (R,S)-1-Acetoxyethyl bromide (3.94 gms; 0.0235 moles) pre-mixedwith ethanol (0.434 gms; 0.0090 moles) was added to a stirred mixture ofcefuroxime acid (5 gms; 0.0118 moles), sodium carbonate (1.0 gms; 0.0090moles) and sodium dihydrogen phosphate (0.21 gms; 0.0017 moles) inN,N-dimethylacetamide (20 ml) at 0-5° C. The mixture was stirred at 0 to20° C. for 180 minutes. Ethyl acetate was added to the reaction mixture,followed by 3% aqueous sodium bicarbonate solution (25 ml). The organiclayer was separated and washed with 10% aqueous sodium chloridesolution. The organic extract was stirred with activated charcoal (0.5gms) for 30 minutes and filtered through a celite bed. The organic layerwas evaporated under vacuum and the solid obtained crystallised from amixture of ethyl acetate/xylene. The crystallised material was filteredand dried at 40 to 45° C. under vacuum to give 5.28 gms (87.8%) of thetitle compound.

[0096] HPLC analysis: Purity (compound I) ≧96.00%; Impurities: Δ² isomer(II) <0.10%, X₁ and X₂—NIL

EXAMPLE-4 Preparation of (R,S-1-Acetoxyethyl-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate(Cefuroxime axetil, I): in presence of calcium monophosphate andn-butanoll

[0097] (R,S)-1-Acetoxyethyl bromide (3.94 gms; 0.0235 moles) pre-mixedwith n-butanol (0.87 gms; 0.0118 moles) was added to a stirred mixtureof cefuroxime acid (5 gms; 0.0118 moles), sodium carbonate (0.93 gms;0.0880 moles) and calcium monophosphate (0.41 gms; 0.00177 moles) inN,N-dimethylacetamide (20 ml) at 0-5° C. The mixture was stirred at 0 to20° C. for 180 minutes. Ethyl acetate was added to the reaction mixture,followed by 3% aqueous sodium bicarbonate solution (25 ml). The organiclayer was separated and washed with 10% aqueous sodium chloridesolution. The organic extract was stirred with activated charcoal (0.5gms) for 30 minutes and filtered through a celite bed. The organic layerwas evaporated under vacuum and the solid obtained crystallised from amixture of ethyl acetate/xylene. The crystallised material was filteredand dried at 40 to 45° C. under vacuum to give 5.29 gms (87.96%) of thetitle compound.

[0098] HPLC analysis: Purity (compound I) ≧96.00%; Impurities: Δ² isomer(II) <0.10%, X₁ and X₂—NIL

EXAMPLE-5 Preparation of (R,S-1-Acetoxyethyl-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate(Cefuroxime axetil, I): in presence of dipotassium hydrogen phosphateand iso-propanol

[0099] (R,S)-1-Acetoxyethyl bromide (3.94 gms; 0.0235 moles) pre-mixedwith iso-propanol (0.70 gms; 0.0118 moles) was added to a stirredmixture of cefuroxime acid (5 gms; 0.0118 moles), potassium carbonate(1.11 gms; 0.0080 moles) and dipotassiumihydrogen phosphate (0.82 gms;0.0047 moles) in N,N-dimethylacetamide (20 ml) at 0-5° C. The mixturewas stirred at 0 to 20° C. for 180 minutes. Ethyl acetate was added tothe reaction mixture followed by 3% aqueous sodium bicarbonate solution(25 ml). The organic layer was separated and washed with 10% aqueoussodium chloride solution. The organic extract was stirred with activatedcharcoal (0.5 gms) for 30 minutes and filtered through a celite bed. Theorganic layer was evaporated under vacuum and the solid obtainedcrystallised from a mixture of ethyl acetate/xylene. The crystallisedmaterial was filtered and dried at 40 to 45° C. under vacuum to give5.28 gms (87.8%) of the title compound.

[0100] HPLC analysis: Purity (compound I) ≧96.00%; Impurities: Δ² isomer(II) <0.10%, X₁ and X₂—NIL

EXAMPLE-6

[0101] Preparation of (R,S-1-Acetoxyethyl-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate(Cefuroxime axetil, I): in presence of sodium pyrophosphate andiso-butanol

[0102] (R,S)-1-Acetoxyethyl bromide (3.94 gms; 0.0235 moles) pre-mixedwith iso-butanol (0.87 gms; 0.0118 moles) was added to a stirred mixtureof cefuroxime acid (5 gms; (0.0118 moles), sodium carbonate (1.00 gms;0.0090 moles) and sodium pyrophosphate (1.25 gms; 0.0047 moles) inN,N-dimethylacetamide (20 ml) at 0-5° C. The mixture was stirred at 0 to20° C. for 180 minutes. Ethyl acetate was added to the reaction mixture,followed by 3% aqueous sodium bicarbonate solution (25 ml). The organiclayer was separated and washed with 10% aqueous sodium chloridesolution. The organic extract was stirred with activated charcoal (0.5gms) for 30 minutes and filtered through a celite bed. The organic layerwas evaporated under vacuum and the solid obtained crystallised from amixture of ethyl acetate/xylene. The crystallised material was filteredand dried at 40 to 45° C. under vacuum to give 5.28 gms (87.8%) of thetitle compound.

[0103] HPLC analysis: Purity (compound I) ≧96.00%; Impurities Δ² isomer(II) <0.10%,, X₁ and X₂—NIL

1. A process for preparation of cefuroxime axetil of formula (I) in highpurity,

comprising reacting cefuroxime acid of formula (III)

with (R,S)-1-acetoxyethyl bromide of formula (IV),

and a Group I or II metal carbonate in the presence of a compound offormula (V), M_(m)H_(n)P_(q)O_(r)   (V) wherein M is Group I or IImetal; m is 1, 2 or 3; n is 0, 1, 2 or 4; q is 1 or 2 and r is 4, 7 or 8and in the presence of a C₁₋₄ alcohol and in the presence of a polartertiary amide solvent at a temperature ranging from about −30 to +30°C. and subjecting the product thus obtained to desired step ofpurification.
 2. A process as claimed in claim 1 wherein said step ofpurification comprises evaporation of the reaction product followed bycrystallisation.
 3. A process as claimed in claim 1 wherein the polartertiary amide solvent is selected from N,N-dimethylacetamide,N,N-dimethylformamide, N,N-dimethylpropionamide, N,N-diethylacetamide,N,N-diethylformamide and N,N-diethylpropionamide withN,N-dimethylacetamide preferred.
 4. A process as claimed in anyone ofclaims 1 or 2 wherein the metal in the Group I or II metal carbonate isselected from lithium, sodium, potassium, cesium, magnesium and calcium,with sodium and potassium preferred.
 5. A process as claimed in claim 3wherein Group I alkali metal carbonate is preferred over Group II alkalimetal carbonate with sodium carbonate being the most preferred.
 6. Aprocess as claimed in anyone of claims 1 to 4 wherein preferably Group Ialkali metal salts of said metal phosphate, hydrogen phosphate andpolyphosphates are used.
 7. A process as claimed in anyone of claims 1to 5 wherein Group I or II metal in compound of formula (V) is selectedfrom lithium, sodium, potassium, cesium, magnesium and calcium, withsodium preferred.
 8. A process as claimed in anyone of claims 1 to 6wherein the molar ratio of Group I or II metal carbonate is 0.55 to 1.0mole equivalent per mole of compound of formula (III).
 9. A process asclaimed in anyone of claims 1 to 7 wherein the molar ratio of Group I orII metal carbonate is 0.55 to 0.70 mole equivalent per mole of compoundof formula (III).
 10. A process as claimed in anyone of claims 1 to 8wherein the molar ratio of compound of formula (IV) is 1.5 to 2.5 moleequivalent per mole of compound of formula (III).
 11. A process asclaimed in claim 9 wherein the molar ratio of compound of formula (IV)is 1.8 to 2.0 mole equivalent per mole of compound of formula (III). 12.A process as claimed in anyone of claims 1 to 10 wherein the molar ratioof compound of formula (V) is 0.10 to 0.80 mole equivalent per mole ofcompound of formula (III).
 13. A process as claimed in claim 11 whereinthe molar ratio of compound of formula (V) is 0.10 to 0.40 moleequivalent per mole of compound of formula (III).
 14. A process asclaimed in anyone of claims 1 to 12 wherein the C₁₋₄ alcohol is selectedfrom methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanoland tert-butanol, with methanol preferred.
 15. A process as claimed inanyone of claims 1 to 13 wherein the C₁₋₄ alcohol is employed in about0.03 to 0.15 moles per mole of compound of formula (III).
 16. A processas claimed in claim 14 wherein the C₁₋₄ alcohol is employed in about0.04 to 0.11 moles per mole of compound of formula (III).
 17. A processas claimed in anyone of claims 1 to 15 wherein the preferred temperatureis from about −10 to +20° C.
 18. A process as claimed in anyone ofclaims 1 to 16 wherein the solvent for crystallisation is selected formdichloroethane, dichloromethane, ethyl acetate and methyl isobutylketone or a mixture of any of these solvents with hexane, toluene,xylene, diisopropyl ether and tertiarybutylmethyl ether.
 19. A processas claimed in anyone of claims 1 to 17 wherein compounds of formula (I)are obtained in substantially pure form, substantially free of undesired2-cephem derivative of formula (II) and other impurities inpharmacoepically acceptable form.
 20. A process for manufacture of thecompounds of formula (I) in substantially pure form as herein describedand illustrated with reference to the accompanying examples.